In the previous funding period, based on the hypothesis that maintenance of telomere function is critical to MM cell survival, we investigated the mechanisms maintaining telomere function in MM and evaluated inhibitors of telomerase/telomeres as novel therapeutics. We have shown that telomerase activity is increased, while telomere length is shorter, in MM cells and cell lines compared to normal plasma cells, providing a critical therapeutic index for using telomere maintenance mechanism-directed novel therapeutics. We have further evaluated the mechanisms regulating telomerase activity in MM. Specifically, we have identified that the important MM survival signals are also mechanisms maintaining telomerase activity. We have demonstrated that IL-6 and IGF-1, which induce MM cell proliferation and survival, also increase telomerase activity; these cytokines augment telomerase activity through NFkB-mediated upregulation of both hTERT mRNA and protein expression; as well as through Akt-mediated hTERT phosphorylation and activation. We have also gone on to show that hsp90 complexes with and modulates telomerase activity; conversely, inhibition of hsp90 by 17-AAG leads to inhibition of telomerase activity. Finally, we have evaluated the effects of various inhibitors of telomerase in MM and identified efficacy of GRN163L, an antisense lipidated oligonucleotide hTERT inhibitor, both in vitro as well as in vivo in a murine model of human MM. In this renewal application, we are initiating a phase I study of GRN163L in relapsed and relapsed refractory MM, we will evaluate the clinical and molecular effects of GRN163L in myeloma; as well as identify agents that are synergistic with telomerase inhibition in preclinical in vitro and in vivo models. The molecular correlates of response versus resistance identified in the single agent clinical study, coupled with preclinical identification of combinations with synergistic anti-MM activity, will provide the framework for combination clinical trials. To this end, the following aims will be pursued: Specific Aim 1: To investigate safety, efficacy, and molecular correlates of telomerase-targeting GRN163L therapy in patients with relapsed or refractory MM; Specific Aim 2: To define rationally-based combinations of telomerase inhibitor and novel agents which mediate synergistic MM cytotoxicity in vitro; and Specific Aim 3: To define the in vivo efficacy of telomerase inhibitor combination therapies in murine models of human MM for translation to derived clinical studies.